The present invention relates to a drug formulation that is useful for the treatment and suppression of systemic infections, for example those caused by Aspergillus and Fusarium species.
Disseminated fungal infections constitute one of the most difficult challenges for clinicians caring for patients with hematological cancer (1). While the incidence of hematogenous candidiasis has been significantly reduced with the introduction of fluconazole prophylaxis, the opportunistic molds have became the leading cause of infectious mortality in this patient population (2). Aspergillosis clearly remains the most common mold infection in patients with hematological cancer. However, new opportunistic pathogens have now emerged as a cause of life-threatening infection worldwide. The most frequently reported of these pathogens is Fusarium (3–7). Infection with Fusarium is associated with a very high mortality and is typically refractory to amphotericin B. Since infection with this organism may mimic aspergillosis, patients are usually treated with Amphotericin B (AMB), an agent with poor activity against Fusariosis. In addition, the airways are the most common primary site of inoculation and infection and are almost always involved in disseminated disease (3–7). Hence, any drug with good activity against Fusariosis (particularly if it is also active against Aspergillosis) that could be given parenterally and also through aerosolization or nebulization will significantly improve our therapeutic armamentarium.
In addition to being ineffective against Fusariosis, Amphotericin B, the first-line treatment for documented or suspected systemic mold infections carries with it common (>75% of treated subjects), substantial and frequently dose-limiting nephrotoxicity, requiring at times hemodialysis. The acute infusion-related adverse events (severe shaking chills, fever, nausea, vomiting, headache) are quite troublesome to patients. Other serious side effects, such as cardiac arrhythmias, bone marrow suppression, neuropathies, and convulsions are also encountered with the use of AMB, although less frequently (8). The introduction of liposomally encapsulated AMB was anticipated to improve the control of systemic fungal infections (9,10). Its administration changed the drug's biodistribution, allowing significantly higher doses to be delivered with (hopefully) better anti-fungal effects, without encountering serious nephrotoxicity (11–13). In spite of an increased renal tolerance to liposomal AMB compared with the parent drug, this new formulation has several limitations, including its high cost (presently around $800 per day) which has limited its use, its toxicity profile which is identical to that of Amphotericin B (except for the kidney toxicity) and the fact that there is no evidence that this new drug formulation has actually improved the ultimate control rate of serious mycotic/mold infections. Liposomal AMB has recently received federal approval for routine clinical use in the U.S.
The only important clinically available alternative to AMB for the treatment of systemic mold infections is itraconazole (Sporinox™) (13, 14, 15). This agent is presently available exclusively as an oral preparation that is only erratically absorbed from the intestinal tract, yielding variable plasma concentrations with highly unpredictable anti-fungal activity (13) and has little or no activity against Fusarium. This bioavailability problem is particularly difficult to manage in bone marrow transplant (BMT) patients who are at highest risk for invasive mold infections. Such patients typically have severe mucositis that interferes with their ability to swallow the itraconazole capsule and also impairs the already erratic intestinal absorption of the drug. In addition, these patients commonly receive antacids or H2 blockers, both agents known to interfere with the absorption of itraconazole.
Based on the above considerations, the development of an effective antimycotic agent with low normal organ toxicity. high bioavailability, predictable pharmacokinetics after parenteral administration, and activity against both Fusarium and Aspergillus appears highly desirable. Pimaricin, or natamycin (FIG. 1) would fulfill the criterion of being an effective anti-fungal agent, exerting significant activity against molds particularly Fusarium and Aspergillus. It was first isolated in 1955 from a strain of Streptomyces (15). Pimaricin exhibited a wide range of in vitro activity against fungi, yeast, and trichomonads (15, 16, 17). The drug was found to have little or no toxicity after oral administration, being virtually non-absorbable from the gastrointestinal tract (16, 17). However, the lack of solubility of pimaricin in various solvents, both aqueous and organic, compatible with human administration has severely restricted its use in clinical medicine. Pimaricin's medical utilization is currently confined to the topical treatment of corneal fungal infections (18) and the prevention of such infections in contact-lens users. In contrast, pimaricin's prominent chemical stability paired with its apparent lack of intestinal absorption and systemic toxicity formed the basis for its FDA-approved use in the food industry, where it is used to prevent the proliferation of (aflatoxin-producing) molds (19).
A parenterally acceptable, nontoxic formulation of pimaricin would be potentially beneficial not only for cancer patients, but also for other groups of immunocompromised patients, e.g. those suffering from HIV and those having recently undergone open heart surgery, all of which are commonly targets for opportunistic infections.
Past attempts to solubilize pimaricin in vehicles that are safe for intravascular administration in humans have all failed, despite the hard work by Stuyk and others (15, 16, 17). Thus, Korteweg and coworkers attempted to solubilize the drug by mixing it with a complex polysaccharide (16). Although the water-solubility of this formulation increased dramatically, its antifungal in vitro activity decreased to about ⅓ of that of native natamycin. Further, this preparation is comparatively toxic in experimental animals, and it was therefore deemed unsuitable for systemic parenteral administration in humans (15).